- 學位論文
反覆性著床失敗之不孕症患者與靜脈注射免疫球蛋白治療成果之探討
Successful Clinical Outcomes of Intravenous Immunoglobulin Treatment in Women with Repeated Implantation Failure
摘要
試管嬰兒技術是一種利用體外完成受精的人工生殖技術，是目前不孕症的各種治療方法中成功率最高的方式。將卵子與精子取出後在胚胎實驗室裡培養，受精作用後再將胚胎植入子宮內著床。雖然試管嬰兒技術在過去十年經歷很多進化而達到很好的療效，但仍有一部分的反覆性著床失敗的不孕症患者無法獲得良好的臨床成效。近年來母體免疫反應在不明原因的反覆性著床失敗與流產已經慢慢被證明有關聯。靜脈注射免疫球蛋白是目前認為可以應用在治療反覆性流產的不孕症患者身上，可能的機轉為減少周邊血液自然殺手細胞數量與抑制自然殺手細胞的細胞毒性。但是目前關於使用靜脈注射免疫球蛋白來治療反覆性著床失敗的不孕症患者，相關文獻太少，且對懷孕活產率的影響仍有爭議。因此，本研究探討反覆性著床失敗患者在早期濾泡期周邊血液CD56+CD16+自然殺手細胞的數目與靜脈注射免疫球蛋白治療成功的臨床成果之關聯性。希望可以在臨床上藉由參考不孕症患者在早期濾泡期周邊血液CD56+CD16+自然殺手細胞的數目，來決定哪些患者對於靜脈注射免疫球蛋白治療可以達到最大的療效。 本研究在反覆性著床失敗患者的月經週期第2–3天，將早期濾泡期的周邊血液CD56+CD16+自然殺手細胞百分比用於評估靜脈注射免疫球蛋白對人工輔助生殖技術週期的影響。本研究共收案283名反覆性著床失敗患者，這些患者至少經歷3次以上人工輔助生殖技術療程失敗，且每次至少植入2個高品質胚胎。我們使用周邊免疫學特徵的接收者操作特徵曲線分析（receiver operating characteristic curve analysis）來預測分組條件，發現影響人工輔助生殖技術懷孕結果的臨界值為CD56+CD16+自然殺手細胞10.6%。於是，我們比較早期濾泡期的周邊血液CD56+CD16+自然殺手細胞≤10.6%和>10.6%兩組間的胚胎著床成功率和懷孕率。 邏輯回歸分析（logistic regression analysis）和接收者操作特徵曲線分析顯示，在初期濾泡期的周邊血液中CD56＋CD16+自然殺手細胞≤10.6％的患者在沒有使用靜脈注射免疫球蛋白治療的反覆性著床失敗組中呈現較低的懷孕率。與周邊血液中CD56+CD16+自然殺手細胞>10.6%組的著床率和懷孕率（分別為24.9%和48.0%）相比，周邊血液中CD56+CD16+自然殺手細胞≤10.6%且未進行IVIG治療的患者呈現出較低的著床率和懷孕率（分別為12.3%和30.3%，P<0.05）。此外，與Non-IVIG組的著床率，懷孕率和活產率（12.3%，30.3%和22.7%，P<0.05）相比，在胚胎植入之前開始IVIG治療的CD56+CD16+自然殺手細胞≤10.6%的患者具有更高的著床率，懷孕率和活產率（分別為27.5%，57.4%和45.6%，P<0.05）。 我們的研究結果說明，在初期濾泡期的周邊血液中CD56+CD16+自然殺手細胞的低百分比（≤10.6%）可能是降低反覆性著床失敗患者懷孕率和著床成功率的潛在指標，而使用靜脈注射免疫球蛋白治療可能會使該亞組受益。
並列摘要
In vitro fertilization (IVF) is a type of assisted reproductive technology (ART) used for infertility treatment. It involves collecting eggs and spermatozoa from a couple and placing them in a laboratory dish, where fertilization takes place. In the past decade, limited success rates in IVF have prompted inquiry into the maternal immune response to embryo implantation. Intravenous immunoglobulin (IVIG) treatment is applied to patients with recurrent miscarriage and high natural killer (NK) cell profile. However, there are relative rare literature that explore the application of IVIG treatment for patients with repeat implantation failure (RIF), which may be related to strict selection of embryos by the endometrium. In our research, we want to demonstrate that IVIG treatment are effective for patients with RIF in ART cycles. The percentage of peripheral CD56+CD16+ NK cells in the early follicular phase on days 2-3 of the menstrual cycle in RIF patients was used to evaluate the impact of IVIG treatment on ART cycles. A total 283 patients with RIF consisting of at least 3 ART failures and at least 2 high quality embryo transfers were recruited. Logistic regression and receiving operating characteristic curve analyses for the peripheral immunological profile were completed to predict implantation success and compare the implantation and pregnancy rates between groups with ≤10.6% and >10.6% of CD56+CD16+ NK cells in the early follicular phase. The logistic regression and receiving operating characteristic curve analyses showed that patients with ≤10.6% of peripheral CD56+CD16+ NK cells in the early follicular phase showed a lower pregnancy rate within the RIF group without IVIG. Patients with peripheral CD56+CD16+ NK cells ≤10.6% and without IVIG treatment showed significantly lower implantation and pregnancy rates (12.3% and 30.3%, respectively, P<0.05) when compared with the CD56+CD16+ NK cells >10.6% group (24.9% and 48.0%, respectively). Furthermore, the patients with CD56+CD16+ NK cells ≤10.6% given IVIG starting before embryo transfer had significantly higher implantation, pregnancy and live birth rates (27.5%, 57.4% and 45.6%, respectively, P<0.05) when compared with the non-IVIG group (12.3%, 30.3% and 22.7%, respectively, P<0.05). The results suggest that the immune profile of lymphocytes may intimately cross-talk with endometrium and then influence the embryo selection by the endometrium in patients with RIF. Our results showed that a low percentage of peripheral CD56+CD16+ NK cells (≤10.6%) in the early follicular phase is a potential indicator of reduced pregnancy and implantation success rates in RIF patients, and IVIG treatment would likely benefit this patient subgroup.